KR102087661B1 - Composition for prevention or treatment of chronic obstructive pulmonary disease comprising GEBR-7B compound - Google Patents
Composition for prevention or treatment of chronic obstructive pulmonary disease comprising GEBR-7B compound Download PDFInfo
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- KR102087661B1 KR102087661B1 KR1020180088058A KR20180088058A KR102087661B1 KR 102087661 B1 KR102087661 B1 KR 102087661B1 KR 1020180088058 A KR1020180088058 A KR 1020180088058A KR 20180088058 A KR20180088058 A KR 20180088058A KR 102087661 B1 KR102087661 B1 KR 102087661B1
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- South Korea
- Prior art keywords
- chronic obstructive
- pulmonary disease
- obstructive pulmonary
- copd
- present
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- A23V2200/314—Foods, ingredients or supplements having a functional effect on health having an effect on lung or respiratory system
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Abstract
본 발명은 GEBR-7B 화합물의 만성폐쇄성 폐질환 치료제 용도에 관한 것으로, 보다 구체적으로 본 발명은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물; 및 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품에 관한 것이다.The present invention relates to the use of a GEBR-7B compound for treating chronic obstructive pulmonary disease, and more particularly, the present invention comprises a GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient, chronic obstructive pulmonary disease (COPD) Pharmaceutical compositions for the prophylaxis or treatment of; And it relates to a health functional food for the prevention or improvement of chronic obstructive pulmonary disease (COPD).
Description
본 발명은 GEBR-7B 화합물의 만성폐쇄성 폐질환 치료제로서의 용도에 관한 것이다. The present invention relates to the use of a GEBR-7B compound as a therapeutic agent for chronic obstructive pulmonary disease.
만성폐쇄성 폐질환(chronic obstructive pulmonary disease, COPD)은 폐의 비정상적인 염증반응으로 기도가 좁아지는 폐질환 중 하나이다. 만성폐쇄성 폐질환은 주로 유해입자나 가스의 흡입에 의해 발생하게 되며, 특히 흡연이 주요 원인으로 알려져 있다. 현재 우리나라의 40세 이상 만성폐쇄성 폐질환 유병률은 해마다 증가하는 추세이며, 또한 전 세계적으로도 만성폐쇄성 폐질환은 유일하게 유병률과 사망률이 증가하는 질환으로, 2020년에는 세계적으로 3번째 사망원인이 될 것으로 추정하고 있다. 흡연은 폐조직 내 강력한 자극물질로 작용하여, 다양한 전염증인자, 성장인자, 산화물질 및 화학주성인자들의 생성을 증가시키며, 염증성 신호전달체계를 활성화시켜 호중구 및 대식세포를 비롯한 많은 염증세포의 유주를 촉진시켜 폐염증을 더욱 악화시키게 된다. 담배연기 및 염증세포들에서 유래된 메탈로프로테나제(metalloproteinase)와 같은 단백분해 효소가 활성화되어 폐 간질조직 내 구성물을 파괴하게 된다. 이는 결국 폐조직의 비정상적인 변화, 이를테면 기도벽의 비후, 폐섬유화를 야기하여 폐기능을 저하시킨다. Chronic obstructive pulmonary disease (COPD) is one of the lung diseases in which the airways are narrowed due to abnormal inflammatory reactions of the lungs. Chronic obstructive pulmonary disease is mainly caused by inhalation of harmful particles or gases, and smoking is known as a major cause. Currently, the prevalence of chronic obstructive pulmonary disease over 40 years old in Korea is increasing year by year, and chronic obstructive pulmonary disease is the only disease in the world where the prevalence and mortality increase. It is estimated. Smoking acts as a powerful stimulant in the lung tissue, increasing the production of various infectious agents, growth factors, oxides and chemotactic factors, and activating the inflammatory signaling system to stimulate inflammatory cells, including neutrophils and macrophages. To promote pulmonary inflammation worse. Proteolytic enzymes, such as metalloproteinases derived from tobacco smoke and inflammatory cells, are activated to destroy components in lung interstitial tissue. This in turn causes abnormal changes in lung tissue, such as thickening of the airway wall, pulmonary fibrosis, which impairs lung function.
따라서 만성폐쇄성 폐질환의 예방 및 치료를 위하여, 질병의 주요 원인인 폐 염증의 개선을 중점에 두고 다양한 물질들의 개발이 이뤄져 오고 있다. 그 중, 천식치료와 유사하게 만성폐쇄성 폐질환의 염증개선을 위한 스테로이드 제제 및 항생제의 치료는 매우 매력적인 치료방법이 될 수 있다. 그러나 스테로이드제제 및 항생제의 경우, 면역억제 및 면역관용 등으로 인한 많은 부작용이 발생할 수 있기 때문에 장기간 치료를 필요로 하는 만성폐쇄성 폐질환 환자에게는 적합하지 않다는 제한점이 있다.Therefore, for the prevention and treatment of chronic obstructive pulmonary disease, the development of various substances have been made with an emphasis on the improvement of pulmonary inflammation which is the main cause of the disease. Among them, the treatment of steroid preparations and antibiotics for the improvement of inflammation of chronic obstructive pulmonary disease can be a very attractive treatment method. However, since steroids and antibiotics can cause many side effects due to immunosuppression and immune tolerance, they are not suitable for patients with chronic obstructive pulmonary disease requiring long-term treatment.
그러므로 부작용이 없으면서도 보다 근본적으로 만성폐쇄성 폐질환에 대한 치료 효과가 우수한 새로운 치료제의 개발이 필요하다.Therefore, there is a need for the development of a new therapeutic agent that is more effective in treating chronic obstructive pulmonary disease without any side effects.
한편, GEBR-7B는 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime 화합물로도 불리는 물질로서, 기억력 회복 및 알츠하이머 개선 효과가 있음이 알려져 있을 뿐, 다른 약리학적 기능에 대한 연구가 보고된 바 없다.On the other hand, GEBR-7B is also called 3- (Cyclopentyloxy) -4-methoxybenzaldehyde O- (2- (2,6-dimethylmorpholino) -2-oxoethyl) oxime compound, which is known to have a memory recovery and Alzheimer's improvement effect. There have been no studies of other pharmacological functions.
이에 본 발명자들은 GEBR-7B 화합물의 만성폐쇄성 폐질환의 예방 또는 치료 가능성을 확인함으로써 본 발명을 완성하였다. Therefore, the present inventors completed the present invention by confirming the possibility of preventing or treating chronic obstructive pulmonary disease of the GEBR-7B compound.
따라서 본 발명의 목적은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of chronic obstructive pulmonary disease (COPD), comprising a GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명의 다른 목적은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품을 제공하는 것이다.In addition, another object of the present invention to provide a health functional food for the prevention or improvement of chronic obstructive pulmonary disease (COPD), comprising a GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object of the present invention, the present invention comprises a GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for the prevention or treatment of chronic obstructive pulmonary disease (COPD) to provide.
본 발명의 일실시예에 있어서, 상기 화합물은 폐 손상 보호효과 또는 염증성 사이토카인의 생성 억제활성을 갖는 것일 수 있다.In one embodiment of the present invention, the compound may have a protective effect on lung damage or inhibiting the production of inflammatory cytokines.
본 발명의 일실시예에 있어서, 상기 염증성 사이토카인은 IL-6 및 TNF-α일 수 있다.In one embodiment of the invention, the inflammatory cytokine may be IL-6 and TNF-α.
본 발명의 일실시예에 있어서, 상기 만성폐쇄성 폐질환(COPD)은 만성폐쇄성기관지염, 만성세기관지염 또는 폐기종(Emphysema)일 수 있다.In one embodiment of the present invention, the chronic obstructive pulmonary disease (COPD) may be chronic obstructive bronchitis, chronic bronchiolitis or emphysema (Emphysema).
또한, 본 발명은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품을 제공한다.In addition, the present invention provides a health functional food for the prevention or improvement of chronic obstructive pulmonary disease (COPD), comprising the GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 화합물은 상기 화합물은 폐 손상 보호효과 또는 염증성 사이토카인의 생성 억제활성을 갖는 것일 수 있다. In one embodiment of the present invention, the compound may be one having a protective effect on lung damage or inhibiting the production of inflammatory cytokines.
본 발명의 일실시예에 있어서, 상기 만성폐쇄성 폐질환(COPD)은 만성폐쇄성기관지염, 만성세기관지염 또는 폐기종(Emphysema)일 수 있다.In one embodiment of the present invention, the chronic obstructive pulmonary disease (COPD) may be chronic obstructive bronchitis, chronic bronchiolitis or emphysema (Emphysema).
본 발명의 GEBR-7B 화합물은 만성폐쇄성 폐질환의 원인이 되는 염증성 사이토카인의 생성 억제활성이 우수하고, 손상된 폐조직 또는 폐세포를 회복시키는 활성을 가짐으로써, 만성폐쇄성 폐질환의 예방, 치료 및 개선을 위한 조성물로 유용하게 사용될 수 있다. The GEBR-7B compound of the present invention is excellent in inhibiting the production of inflammatory cytokines that cause chronic obstructive pulmonary disease, and has the activity of restoring damaged lung tissue or lung cells, thereby preventing, treating and treating chronic obstructive pulmonary disease. It can be usefully used as a composition for improvement.
도 1은 본 발명의 일실시예에서 PPE 주입에 의한 COPD 유발 마우스 동물모델의 제작 모식도 및 GEBR-7B의 주입시점(0.5mg/kg의 양을 2주간 주입)을 나타낸 도면이다.
도 2는 PPE 주입에 의해 폐 손상된 COPD 유발 마우스의 폐조직(PPE)과 GEBR-7B을 주입한 마우스의 폐조직(GERB,PPE+GERB) 및 정상의 건강한 마우스 폐조직(CTL)을 대상으로 H&E 염색을 통해 폐 손상 정도를 확인한 결과를 나타낸 것이고(2a), 또한 Mean linear intercept Lm (μm) 값을 그래프로 나타낸 것이다(2b).
도 3은 COPD 유발 마우스 동물 모델에서 GERB-7B 처리에 따른 염증성 사이토카인의 분비 억제 효과를 확인한 결과로서, 3a는 BALF 세포를 대상으로 Giemsa 염색을 수행한 결과를 나타낸 것이고, 3b 및 3c는 염증성 사이토카인의 생성 정도를 확인한 결과를 나타낸 것이다.1 is a view showing a schematic diagram of the production of COPD-induced mouse animal model by PPE injection in one embodiment of the present invention and the time of injection of GEBR-7B (injection amount of 0.5mg / kg for 2 weeks).
FIG. 2 shows H & E of lung tissue (PPE) of lung damaged COPD-induced mice by PPE injection and lung tissue (GERB, PPE + GERB) and normal healthy mouse lung tissue (CTL) of mice injected with GEBR-7B. It shows the result of confirming the degree of lung damage through staining (2a), and also the graph of Mean linear intercept Lm (μm) value (2b).
3 is a result confirming the inhibitory effect of the inflammatory cytokine secretion according to GERB-7B treatment in a COPD-induced mouse animal model, 3a shows the results of Giemsa staining on BALF cells, 3b and 3c inflammatory cytokines It shows the result of checking the generation level of the cain.
본 발명은 GERB-7B 화합물의 만성폐쇄성 폐질환의 치료제로서의 신규 용도를 규명한 점에 특징이 있다.The present invention is characterized by identifying a novel use of the GERB-7B compound as a therapeutic agent for chronic obstructive pulmonary disease.
따라서 본 발명은 GERB-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물을 제공한다. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating chronic obstructive pulmonary disease (COPD) comprising a GERB-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 GERB-7B 화합물은 앞서 종래 기술에서도 기재한 바와 같이, 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime 화합물로도 불리는 물질로서, 기억력 회복 및 알츠하이머 개선 효과가 있음이 알려져 있을 뿐, 만성폐쇄성 폐질환(COPD)과의 관련성에 대한 연구는 보고된 바가 없다. The GERB-7B compound is a substance also called 3- (Cyclopentyloxy) -4-methoxybenzaldehyde O- (2- (2,6-dimethylmorpholino) -2-oxoethyl) oxime compound, as described in the prior art, It is known that there is a recovery and ameliorating Alzheimer's effect, and there has been no report on the association with chronic obstructive pulmonary disease (COPD).
본 발명의 상기 GERB-7B 화합물은 바람직하게 하기 화학식 1의 구조식을 갖는 화합물일 수 있다. The GERB-7B compound of the present invention may be preferably a compound having the structural formula of Formula 1.
<화학식 1><Formula 1>
본 발명의 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.The compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, Xylene Sulfonate, Phenyl Acetate, Phenylpropionate, Phenyl Butyrate, Citrate, Lactate, β-hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
또한, 본 발명의 약학적 조성물은 약제학적으로 허용 가능한 담체를 추가로 포함할 수 있다. In addition, the pharmaceutical compositions of the present invention may further comprise a pharmaceutically acceptable carrier.
한편, 만성폐쇄성 폐질환(Chronic Obstructive Pulmonary Disease, COPD)은 비가역적인 기도의 폐색을 동반한다는 점에서 천식과 다르며 기도 및 폐실질 염증에 의한 세기관지 및 폐실질의 병리학적 변화에 의해 발생하는 병으로, 폐쇄성 세기관지염 및 폐기종(폐실질 파괴)을 특징으로 한다. 만성폐쇄성 폐질환(Chronic Obstructive Pulmonary Disease)의 종류에는 만성폐쇄성 기관지염(Chronic obstructive bronchitis), 만성 세기관지염(Chronic bronchiolitis) 및 폐기종(Emphysema)이 있다. 본 발명의 조성물의 대상질환은 바람직하게는 만성폐쇄성 폐질환일 수 있으나, 본 발명이 적용가능한 비가역적인 기도의 폐색을 동반하며 기도 및 폐실질 염증에 의한 세기관지 및 폐실질의 병리학적 변화에 의해 발생하는 병에 제한되는 것은 아니다.Chronic Obstructive Pulmonary Disease (COPD), on the other hand, differs from asthma in that it is accompanied by irreversible airway obstruction and is caused by pathological changes in the bronchioles and pulmonary parenchyma by airway and lung parenchymal inflammation. Obstructive bronchiolitis and emphysema (pulmonary parenchymal destruction). Types of chronic obstructive pulmonary disease include chronic obstructive bronchitis, chronic bronchiolitis and emphysema. The disease of interest of the composition of the present invention may preferably be chronic obstructive pulmonary disease, but is accompanied by irreversible obstruction of airway to which the present invention is applicable and caused by pathological changes of bronchioles and lung parenchyma by airway and lung parenchymal inflammation. It is not limited to the disease.
특히 본 발명에서는 GERB-7B 화합물이 만성폐쇄성 폐질환을 예방, 개선 또는 치료할 수 있음을 확인하였는데, 구체적으로 본 발명의 일실시예에 의하면, 만성폐쇄성 폐질환이 유발된 마우스 동물모델을 대상으로, 본 발명의 GERB-7B 화합물을 주입한 군과 주입하지 않은 군을 대상으로 폐 조직의 손상 정도를 분석하였다. In particular, the present invention confirmed that the GERB-7B compound can prevent, improve or treat chronic obstructive pulmonary disease. Specifically, according to an embodiment of the present invention, a mouse animal model in which chronic obstructive pulmonary disease is induced, The extent of lung tissue damage was analyzed in the group injected with and without the GERB-7B compound of the present invention.
그 결과, PPE의 주입으로 만성폐쇄성 폐질환이 유발된 마우스 폐의 폐포 벽은 건강한 마우스(CTL)의 폐 조직과 비교하여 파괴되어 확대된 것으로 나타났으며, 폐포 영역의 폭을 정량분석한 결과, PPE을 주사한 마우스에서는 Lm이 유의하게 증가한 것으로 나타난 반면, GEBR-7B을 투여한 마우스는 PPE에 노출된 마우스의 폐와 비교하여 폐 손상이 회복된 것으로 나타났다.As a result, the alveolar wall of the mouse lung induced with chronic obstructive pulmonary disease caused by the injection of PPE was found to be enlarged by destruction compared to the lung tissue of the healthy mouse (CTL). Lpem increased significantly in mice injected with PPE, whereas mice treated with GEBR-7B recovered lung damage as compared to the lungs of mice exposed to PPE.
또한, 본 발명의 다른 일실시예에서는 만성폐쇄성 폐질환이 유발된 마우스의 기관지폐포세척액(bronchoalveolar lavage fluid ; BALF)을 대상으로 염증성 사이토카인의 생성정도를 분석하였는데, GEBR-7B을 투여한 마우스 군이 투여하지 않은 마우스 군에 비해 염증반응의 지표인 대식세포가 감소한 것으로 나타났고, 염증성 사이토카인인 IL-6 및 TNF-α의 수준도 감소된 것으로 나타났다.In another embodiment of the present invention, the bronchoalveolar lavage fluid (BALF) of the mice with chronic obstructive pulmonary disease was analyzed for the production of inflammatory cytokines. Compared with the group of mice not administered this group, macrophages, which are indicative of inflammatory responses, were decreased, and levels of inflammatory cytokines IL-6 and TNF-α were also reduced.
TNF-α 및 IL-6와 같은 염증성 사이토카인과 케모카인들은 폐혈관 순환에서부터 폐포로까지 호중구의 트래피킹(trafficking) 활성에 관여하는 것으로 알려져 있다. 이들은 모두 염증과 관련된 사이토카인 또는 케모카인들로서, 만성폐쇄성 폐질환의 경우, 호중구 수가 증가하며 이러한 염증성 사이토카인 또는 케모카인이 분비된다. 이러한 분비 물질은 기도에 염증을 유발하게 되고, 근육벽이 두꺼워지며, 점액 분비가 증가하여 기관지 폐쇄가 나타난다. 기관지가 폐쇄되면 폐포는 확장되고 손상되어 산소와 이산화탄소의 교환능력이 손상을 받게 되며, 호흡부전발생이 높아지게 된다. 특히, 이들 염증성 사이토카인 또는 케모카인은 COPD를 앓고 있는 환자들에게서 발현이 증가됨이 밝혀져, 만성폐쇄성 폐질환과의 원인 요소로 알려져 있다. Inflammatory cytokines and chemokines such as TNF-α and IL-6 are known to be involved in the trafficking activity of neutrophils from pulmonary vascular circulation to alveoli. These are all cytokines or chemokines associated with inflammation, in the case of chronic obstructive pulmonary disease, the neutrophil count increases and these inflammatory cytokines or chemokines are secreted. These secretory substances cause inflammation in the airways, thicken the muscle walls, and increase mucus secretion resulting in bronchial obstruction. When the bronchus is closed, the alveoli expand and become damaged, impairing the exchange capacity of oxygen and carbon dioxide, and increasing respiratory failure. In particular, these inflammatory cytokines or chemokines have been found to have increased expression in patients suffering from COPD, and are known to be a causative factor of chronic obstructive pulmonary disease.
따라서, 본 발명의 GEBR-7B 화합물은 외부 유해물질로부터 야기되는 폐포의 확장을 억제하여 폐 손상을 감소시키는 효과가 있고, 염증성 사이토카인의 생성 억제활성을 갖는 바, 만성폐쇄성 폐질환 반응을 억제시킬 수 있다. Therefore, the GEBR-7B compound of the present invention has the effect of reducing lung damage by inhibiting the expansion of alveoli caused by external harmful substances, and having the inhibitory activity of the production of inflammatory cytokines, thereby suppressing chronic obstructive pulmonary disease reaction. Can be.
본 발명에서 "만성폐쇄성 폐질환"은 유해한 입자나 가스의 흡입에 의해 폐에 비정상적인 염증 반응이 일어나면서 이로 인해 점차 기류 제한이 진행되어 폐 기능이 저하되고 호흡곤란을 유발하게 되는 호흡기 질환을 말한다. 만성폐쇄성 폐질환의 주된 증상은 만성적인 기침 또는 만성적인 가래(객담)을 비롯하여 호흡곤란 등이 있으며, 베타항진제, 항콜린제, 메틸잔틴계 등의 기관지 확장제 또는 부신피질 호르몬 흡입제 등이 대표적인 치료제로 사용된다. 본 발명에서 상기 만성폐쇄성 폐질환은 바람직하게는 만성 기관지염(chronic bronchitis) 또는 폐기종(emphysema)일 수 있으나, 이에 제한되지 않는다.In the present invention, "chronic obstructive pulmonary disease" refers to a respiratory disease in which abnormal inflammatory reactions occur in the lungs due to inhalation of harmful particles or gases, thereby gradually limiting air flow, thereby lowering lung function and causing respiratory distress. The main symptoms of chronic obstructive pulmonary disease include chronic cough or chronic sputum (sputum), shortness of breath, and beta-inhibitors, anticholinergic agents, bronchodilators such as methylxanthine, or corticosteroid inhalation. do. In the present invention, the chronic obstructive pulmonary disease may preferably be chronic bronchitis or emphysema, but is not limited thereto.
본 발명에서 용어, "만성 기관지염(chronic bronchitis)"이란, 2년 연속, 1년에 3개월 이상 가래가 있고 기침이 지속되는 질환을 의미한다. 흡연, 대기오염, 직업적 노출 등의 자극에 의한 기관지 손상이 원인으로 추정되고 있으며, 주요 증상으로는 만성 기침, 가래, 운동시 호흡곤란 등이 있다. 또한, 만성폐쇄성 폐질환의 특징인 급성 악화가 있을 수 있으며, 이때에는 수 시간에서 수일 사이 호흡곤란이 빠르게 악화되고 가래의 양이 늘어나거나 가래의 성상이 점액성에서 화농성으로 변하면서 진한 노란색이나 푸르스름한 색을 띄게 되고 점도가 높아져 뱉어내기 힘들어진다.As used herein, the term "chronic bronchitis" refers to a disease in which there is more than three months of sputum and a cough lasts for two consecutive years. Bronchial damage caused by stimulation such as smoking, air pollution and occupational exposure is presumed to be the cause. The main symptoms include chronic coughing, sputum and dyspnea during exercise. In addition, there may be acute deterioration, which is characteristic of chronic obstructive pulmonary disease, in which breathing problems worsen rapidly from hours to days and the amount of sputum increases, or the appearance of sputum changes from mucus to purulent, dark yellow or bluish. The color becomes high and the viscosity increases, making it hard to spit out.
본 발명에서 용어, "폐기종(emphysema)"이란, 종말 세기관지(terminal bronchiole) 원위부 공기공간(airspace)의 파괴로 인하여 비정상적이며 영구적인 말초 기도 및 폐포의 확장상태를 의미한다. 유해 입자와 가스의 흡입에 의하여 발생하며, 임상적으로 가장 의미있는 위험인자는 흡연으로 알려져 있다. 주요 증상으로는 만성적인 기침과 가래, 호흡곤란 등이 있다. As used herein, the term "emphysema" refers to an abnormal and permanent expansion of the peripheral airways and alveoli due to destruction of the terminal bronchiole distal airspace. Caused by inhalation of harmful particles and gases, the most clinically significant risk factor is known as smoking. The main symptoms include chronic cough, sputum and dyspnea.
본 발명에서 사용된 용어, "예방"은 본 발명에 따른 조성물의 투여로 만성폐쇄성폐질환을 억제 또는 지연시키는 모든 행위를 말한다. As used herein, the term "prevention" refers to any action that inhibits or delays chronic obstructive pulmonary disease by administration of a composition according to the present invention.
본 발명에서 사용된 용어, "치료"는 본 발명에 따른 조성물의 투여로 만성폐쇄성 폐질환의 발병을 억제 또는 지연시키는 모든 행위를 말한다. As used herein, the term "treatment" refers to any action that inhibits or delays the development of chronic obstructive pulmonary disease by administration of a composition according to the present invention.
본 발명의 약학적 조성물은 단일제제로도 사용할 수 있으며, 공인된 만성폐쇄성폐질환 억제 효과를 가진다고 알려진 약물을 추가로 포함하여 복합제제로 제조하여 사용할 수 있다. The pharmaceutical composition of the present invention may also be used as a single agent, and may be prepared and used as a complex formulation, further including a drug known to have a recognized chronic obstructive pulmonary disease inhibitory effect.
상기 "약학적으로 허용 가능한"이란 생물체를 상당히 자극하지 않고 투여 활성 물질의 생물학적 활성 및 특성을 저해하지 않는 것을 의미한다. By "pharmaceutically acceptable" is meant that it does not significantly irritate the organism and does not inhibit the biological activity and properties of the administered active substance.
약학적으로 허용 가능한 담체를 포함하는 본 발명의 약학적 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로오스 (sucrose) 또는 락토오스 (lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다. The pharmaceutical composition of the present invention comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다. 또한, 본 발명의 약학적 조성물은 약제학적으로 유효한 양의 상기 본 발명의 화합물을 포함할 수 있다. 본 발명에서 용어 "약제학적으로 유효한 양"은 의학적 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용을 유발하지 않으면서 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 바람직하게는 본 발명에 따른 약학적 조성물은 상기 본 발명의 화합물을 약학적 조성물에 0.001 내지 1500 ㎍/ml로 포함될 수 있으며, 보다 바람직하게는 0.001 내지 1000 ㎍/ml으로 포함될 수 있다. The pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solvents, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have one formulation. In addition, the pharmaceutical composition of the present invention may include a pharmaceutically effective amount of the compound of the present invention. As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type and severity of the subject, the severity, age, sex, activity of the drug. , Drug sensitivity, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts. The pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of these factors into consideration it is important to administer an amount that can achieve the maximum effect in a minimum amount without causing side effects and can be readily determined by one skilled in the art. Preferably, the pharmaceutical composition according to the present invention may include the compound of the present invention in the pharmaceutical composition at 0.001 to 1500 μg / ml, more preferably at 0.001 to 1000 μg / ml.
나아가 본 발명은 본 발명의 GEBR-7B 화합물을 포함하는 약학적 조성물을 COPD의 예방 또는 치료가 필요한 개체에 투여하여 COPD를 예방 또는 치료하는 방법을 제공한다. Furthermore, the present invention provides a method for preventing or treating COPD by administering a pharmaceutical composition comprising the GEBR-7B compound of the present invention to a subject in need of preventing or treating COPD.
본 발명에서 상기 개체는 만성폐쇄성 폐질환이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미하며, 본 발명의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물을 만성폐쇄성 폐질환 의심 개체에 투여함으로써, 개체를 효율적으로 치료할 수 있다. 구체적으로, 상기 개체는 인간뿐만 아니라 이와 유사한 증상의 치료를 필요로 하는 소, 말, 양, 돼지, 염소, 낙타, 영양, 개, 고양이 등의 포유동물일 수 있으나, 이에 제한되지는 않는다.In the present invention, the subject means all animals, including humans, who may or may develop chronic obstructive pulmonary disease, and suspect the chronic obstructive pulmonary disease of the pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof. By administering to an individual, the individual can be treated efficiently. Specifically, the subject may be, but is not limited to, a mammal, such as a human, a cow, a horse, a sheep, a pig, a goat, a camel, a antelope, a dog, a cat, etc., which need treatment for a similar symptom.
본 발명에서 사용된 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a patient in any suitable manner, wherein the route of administration of the composition of the present invention is oral or parenteral as long as the target tissue can be reached. Administration can be via a variety of routes.
나아가 본 발명은 GEBR-7B 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품을 제공한다. Furthermore, the present invention provides a health functional food for preventing or improving chronic obstructive pulmonary disease (COPD), comprising the GEBR-7B compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 식품 조성물은 식품학적으로 허용 가능한 담체를 추가로 포함하는 것일 수 있다. The food composition of the present invention may further comprise a food acceptable carrier.
상기 식품 조성물은 만성폐쇄성 폐질환 억제에 도움을 주는 기능을 가질 수 있다. 본 발명의 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함하며, 본 발명의 화합물을 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. The food composition may have a function of helping to suppress chronic obstructive pulmonary disease. The food composition of the present invention includes the form of pills, powders, granules, acupuncture, tablets, capsules or liquids, etc., there is no particular limitation on the kind of food to which the compound of the present invention can be added, for example, various beverages, Chewing gum, tea, vitamin complexes, and dietary supplements.
상기 식품 조성물에는 본 발명의 화합물 이외에도 만성폐쇄성 폐질환 억제활성에 방해가 되지 않는 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학적으로 허용가능한 식품보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. In addition to the compound of the present invention, other ingredients that do not interfere with the inhibitory activity of chronic obstructive pulmonary disease may be added to the food composition, and the kind thereof is not particularly limited. For example, various herbal extracts, food acceptable additives, natural carbohydrates, and the like may be contained as additional ingredients, such as conventional foods.
본 발명에서 사용된 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다. As used herein, the term "food supplement" refers to a component that can be added to food supplements, and can be appropriately selected and used by those skilled in the art as being added to prepare a health functional food of each formulation. Examples of food additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners. , pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, but is not limited to the kind of food additives of the present invention by the above examples.
상기 천연 탄수화물의 예는 포도당, 과당 등의 단당류; 말토스, 수크로스 등의 이당류; 및 덱스트린, 시클로덱스트린 등의 다당류와, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연향미제 (타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 Ａ, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; And sugars such as polysaccharides such as dextrin and cyclodextrin, and xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
본 발명의 식품 조성물에는 건강기능성 식품이 포함될 수 있다. 본 발명에서 사용된 용어 "건강기능성 식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 기능성이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능성 식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다. The food composition of the present invention may include a health functional food. As used herein, the term "health functional food" refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients having useful functions for the human body. Here, functional means to obtain a useful effect for health use such as nutrient control or physiological action on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art. In addition, unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug as a raw material, and can be excellent in portability.
본 발명의 조성물을 건강기능식품에 포함하여 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 건강기능식품 또는 건강기능식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 본 발명의 화합물은 원료 조성물 중 1 ~ 10 중량%, 바람직하게는 5 ~ 10 중량%의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다. When the composition of the present invention is used in a health functional food, the composition may be added as it is or used with other health functional foods or health functional food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment). Generally, in the preparation of foods, the compounds of the present invention are added in an amount of 1 to 10% by weight, preferably 5 to 10% by weight in the raw material composition. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be used below the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능성 식품을 모두 포함한다. There is no particular limitation on the kind of the food. Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, drinks, tea, drink, Alcoholic beverages and vitamin complexes, and includes all of the health functional foods in the conventional sense.
본 발명에서 용어, "개선"은 상기 조성물을 이용하여 만성폐쇄성 폐질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다. In the present invention, the term "improvement" refers to all the actions that improve or benefit the symptoms of the suspected and the onset of chronic obstructive pulmonary disease using the composition.
본 발명의 조성물을 포함할 수 있는 건강기능식품의 종류에는 특별한 제한은 없으며, 구체적인 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있고, 통상적인 의미에서의 건강기능식품을 모두 포함할 수 있으며, 동물을 위한 사료로 이용되는 식품을 포함할 수 있다. There is no particular limitation on the type of health functional food that may include the composition of the present invention, and specific examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, and ice cream. Dairy products, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes, etc., may include all of the health functional foods in the conventional sense, and may include foods used as feed for animals.
또한, 본 발명의 건강기능식품 조성물이 음료의 형태로 사용될 경우에는 통상의 음료와 같이 여러 가지 감미제, 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨, 에리트리톨과 같은 당알콜일 수 있다. 상기 천연 탄수화물의 비율은 이에 제한되지는 않으나, 본 발명의 조성물 100 ㎖ 당 바람직하게는 약 0.01 내지 0.04g, 보다 바람직하게는 0.02 내지 0.03g일 수 있다. 상기 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제 및 사카린, 아스파르탐과 같은 합성 감미제일 수 있다. In addition, when the health functional food composition of the present invention is used in the form of a beverage, it may contain various sweetening agents, flavoring agents or natural carbohydrates, etc. as additional ingredients, as in the general beverage. The natural carbohydrate may be glucose, monosaccharides such as fructose, maltose, disaccharides such as sucrose, polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, erythritol. The ratio of the natural carbohydrate is not limited thereto, but may be preferably about 0.01 to 0.04 g, more preferably 0.02 to 0.03 g per 100 ml of the composition of the present invention. The sweetener may be a natural sweetener such as taumartin, stevia extract and a synthetic sweetener such as saccharin, aspartame.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the nutraceutical composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin , Alcohols, carbonation agents used in carbonated drinks, and the like. Others may contain pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited to these examples.
<준비예><Preparation Example>
시료sample
GEBR-7B은 Calbiochem사 (524748) (Merck KGaA, Darmstadt,Germany)로부터 구입하여 사용하였다. 이들 물질은 DMSO가 1% 미만이 되도록 배지에 용해하여 사용하였다. 일차 항체들로서, p-NF-kB (#3033), p-CREB(#9198), p-ERK1/2 (#4370), ERK1/2 (#4695), p-JNK1/2 (#4668), JNK1/2 (#9252), p-p38 (#4511) and p38 (#9212), β-actin (#3700)에 대한 항체는 Cell Signaling Technology사 (Beverly, MA, USA)로부터 구입해서 사용하였고, p-PKA (sc-32968), p-Akt (sc-8312), Akt(sc-7985), Bcl-2 (sc-492) 및 BAX (sc-7480)은 Santa Cruz Biotechnology사(Santa Cruz, CA, USA)로부터 구입하여 사용하였다. GEBR-7B was purchased from Calbiochem (524748) (Merck KGaA, Darmstadt, Germany). These materials were used by dissolving in the medium so that the DMSO was less than 1%. As primary antibodies, p-NF-kB (# 3033), p-CREB (# 9198), p-ERK1 / 2 (# 4370), ERK1 / 2 (# 4695), p-JNK1 / 2 (# 4668), Antibodies against JNK1 / 2 (# 9252), p-p38 (# 4511) and p38 (# 9212), and β-actin (# 3700) were purchased from Cell Signaling Technology (Beverly, MA, USA), p-PKA (sc-32968), p-Akt (sc-8312), Akt (sc-7985), Bcl-2 (sc-492) and BAX (sc-7480) are manufactured by Santa Cruz Biotechnology (Santa Cruz, CA). , USA).
실험방법Experiment method
실험동물Laboratory animals
8 주령의 C57BL / 6 마우스는 두열 바이오텍(한국)으로부터 입수하여 사용하였고, 강원대학교의 지침에 따라 기관 동물 관리 및 사용위원회(No. KW-150820-1)의 규정된 승인에 따라 실험에 사용하였다. COPD 동물 모델은 돼지 췌장 엘라스타제(porcine pancreatic elastase, PPE)를 기관 내로 주입하여 COPD 이 유발된 마우스 동물 모델을 제조하였으며, PDE4D 억제제인 GEBR-7B는 2 주간 매일 복강 내로 처리하였으며, 마우스를 zoletile로 마취시킨 후, PPE를 주사하여 희생시켰다.Eight-week-old C57BL / 6 mice were obtained from Dooyeol Biotech (Korea) and used for experiments in accordance with the regulatory approval of the Institutional Animal Care and Use Committee (No. KW-150820-1) in accordance with the guidelines of Kangwon National University. . The COPD animal model was prepared by injecting porcine pancreatic elastase (PPE) into the trachea to produce a COPD-induced mouse animal model, and GEBR-7B, a PDE4D inhibitor, was treated intraperitoneally daily for two weeks, and mice were zoletile. After anesthesia, PPE was injected and sacrificed.
ELISAELISA
전염증성 사이토카인 수준은 ELISA 키트(R&D 시스템, TNF-α: DY410 및 IL-6 :DY406)를 이용하여 측정하였다. 모든 항체와 샘플들은 Maxisorp Nunc-immuno 모듈 마이크로 플레이트(Thermo Scientific, MA, USA, 469949)에서 2시간 이상(적어도 18 시간) 동안 코팅하였다. 각 단계는 키트설명서에 따라 수행하였으며, 황산용액 (Sigma-aldrich, MO, USA, 35276)은 반응 중단을 위해 사용하였다. 흡광도는 platEpoch (BioTek, VT, USA) 마이크로 플레이트 분광광도계를 사용하여 450 nm에서 측정하였다.Proinflammatory cytokine levels were measured using an ELISA kit (R & D system, TNF-α: DY410 and IL-6: DY406). All antibodies and samples were coated for at least 2 hours (at least 18 hours) on Maxisorp Nunc-immuno module microplates (Thermo Scientific, MA, USA, 469949). Each step was carried out according to the kit instructions, sulfuric acid solution (Sigma-aldrich, MO, USA, 35276) was used to stop the reaction. Absorbance was measured at 450 nm using a platEpoch (BioTek, VT, USA) microplate spectrophotometer.
조직학적 분석Histological analysis
Zoletil로 마취시킨 마우스는 PPE 주사 후 희생시켰다(2 주). 오른쪽 폐를 고정하기 위해 밤새도록 4 % 파라포름 알데히드 용액에 넣어두었고, 이후 조직을 파라핀으로 임베딩시킨 후, 6μm 단면으로 절단한 다음 헤마톡실린과 에오신(H & E)으로 염색하였다. 폐포의 평균 선형절편(Lm)은 이미지 J 소프트웨어로 측정하였다Mice anesthetized with Zoletil were sacrificed after PPE injection (2 weeks). The right lung was left overnight in 4% paraformaldehyde solution, and then the tissues were embedded with paraffin, cut into 6 μm sections and stained with hematoxylin and eosin (H & E). The average linear section (Lm) of the alveoli was measured by Image J software.
기관지 폐포 세척액 세포 염색Bronchial Alveolar Lavage Cell Staining
Brochealveolar 세척액(BALF)은 기관(trachea)을 통해 22 게이지 정맥 카테터와 1 ML 생리식염수로 격리시켰다. 분리된 유체를 3000rpm에서 10 분간 원심분리 한 후, 상등액을 1.5mL 마이크로 튜브로 수집하였다. 세포 펠릿은 1mL 식염수에 재현탁한 다음, 100-200μL를 폴리-1-라이신으로 코팅된 슬라이드에서 3000g(10 분, Sigma-aldrich, MO, USA)으로 원심분리 하였다. 슬라이드는 지침서에 따라 HEMA 3 염색팩(Fisher Scientific Co LLC, MI, USA, 123-869)을 사용하여 염색하였고, 염색 세포를 현미경(× 200)으로 관찰한 후, 세포수를 측정하였다.Brochealveolar lavage fluid (BALF) was isolated via trachea into a 22 gauge venous catheter and 1 ml physiological saline. The separated fluid was centrifuged at 3000 rpm for 10 minutes, and then the supernatant was collected into a 1.5 mL microtube. Cell pellets were resuspended in 1 mL saline and then centrifuged at 3000 g (10 min, Sigma-aldrich, Mo., USA) on slides coated with poly-1-lysine. Slides were stained using a HEMA 3 staining pack (Fisher Scientific Co LLC, MI, USA, 123-869) according to the instructions, and the stained cells were observed under a microscope (× 200) before measuring the cell number.
통계처리Statistical processing
모든 데이터는 GraphPad prism 5 소프트웨어(GraphPad Software, La Jolla, CA, USA)로 평균 ± 표준 오차로 표기하였다. 각 결과는 일원 분산 분석(one-way ANOVA)으로 테스트 한 후 Bonferroni의 다중 비교 테스트(Multiple Comparison Test)를 3 회 이상 독립적으로 수행하여 분석하였다. 그래프 패드 프리즘 (GraphPad prism) 프로그램에 의해 p <0.05의 값이 통계적으로 유의한 것으로 결정하였다.All data are expressed as mean ± standard error with GraphPad prism 5 software (GraphPad Software, La Jolla, Calif., USA). Each result was tested by one-way ANOVA and analyzed independently by Bonferroni's Multiple Comparison Test three or more times. The value of p <0.05 was determined to be statistically significant by the GraphPad prism program.
<< 실시예Example 1> 1>
만성폐쇄성 폐질환 유발 마우스 모델에서 Chronic Obstructive Pulmonary Disease-Induced Mouse Model GEBRGEBR -7B 처리에 따른 폐 손상 억제 효과 분석Of Lung Injury Inhibitory Effect Following -7B Treatment
C57BL/6 마우스를 대상으로 폐포 상피를 파괴하는 돼지 췌장 엘라스타제 (PPE)를 기관 내로 주입시켜 2 주 동안 PPE로 노출시킨 다음 14 일째에 희생시켰다. 이후 GEBR-7B을 처리한 시료와 처리하지 않은 마우스로부터 폐 조직을 수득한 후, H & E 염색을 통해 폐 조직의 손상 정도를 분석하였다. 이때 COPD가 유발된 마우스 모델 제조 모식도 및 GEBR-7B의 처리 시점을 도 1에 나타내었다. C57BL / 6 mice were injected into tracheal pancreatic elastase (PPE), which destroys the alveolar epithelium, and exposed to PPE for 2 weeks and then sacrificed on
그 결과, 도 2에 나타낸 바와 같이, PPE가 주입된 마우스 폐의 폐포 벽은 건강한 마우스(CTL)의 폐 조직과 비교하여 파괴되어 확대된 것으로 나타났다(도 2a 참조). 또한, 폐포 영역의 폭을 정량화하기 위해 평균 lenear intercept (Lm)을 측정하고 그래픽화 하였는데, PPE을 주사한 마우스에서는 Lm이 유의하게 증가하였고, 양성으로 GEBR-7B을 동시에 투여한 마우스의 Lm 값은 PPE에 노출된 마우스의 폐와 비교하여 폐 손상이 회복된 것으로 나타났다(도 2b 참조).As a result, as shown in FIG. 2, the alveolar wall of the mouse lungs injected with PPE was found to be broken and enlarged as compared to the lung tissue of healthy mice (CTL) (see FIG. 2A). In addition, the mean lenear intercept (Lm) was measured and graphicized to quantify the width of the alveolar region. Lm increased significantly in the mice injected with PPE, and the Lm value of the mice simultaneously receiving positive GEBR-7B Lung damage was recovered as compared to the lungs of mice exposed to PPE (see FIG. 2B).
따라서 이러한 결과를 통해 본 발명자들은 GEBR-7B가 폐 조직의 손상을 보호하는 효과가 있어, 만성폐쇄성 폐질환을 예방, 개선 및 치료할 수 있음을 알 수 있었다. Therefore, the present inventors have found that GEBR-7B has an effect of protecting lung tissue from damage, thereby preventing, improving and treating chronic obstructive pulmonary disease.
<< 실시예Example 2> 2>
만성폐쇄성 폐질환 유발 마우스 모델에서 Chronic Obstructive Pulmonary Disease-Induced Mouse Model GEBRGEBR -7B 처리에 따른 염증반응 억제 효과 분석Inhibition of Inflammatory Response Following -7B Treatment
만성염증은 만성폐쇄성 폐질환(COPD)의 특징 중 하나에 해당하여, 본 발명자들은 만성폐쇄성 폐질환이 유발된 마우스에 GEBR-7B를 처리할 경우, COPD의 특징인 염증 반응이 억제되는지 확인하기 위한 실험을 수행하였다. 이를 위해 기관지폐포세척액(bronchoalveolar lavage fluid ; BALF)에서의 염증 세포를 측정하였다. Chronic inflammation is one of the features of chronic obstructive pulmonary disease (COPD), the inventors of the present invention to determine whether the treatment of GEBR-7B in mice with chronic obstructive pulmonary disease is suppressed the inflammatory response characteristic of COPD The experiment was performed. To this end, inflammatory cells in bronchoalveolar lavage fluid (BALF) were measured.
분석 결과, PPE로 COPD가 유발된 마우스에서는 염증반응의 지표인 대식세포가 증가한 것으로 나타났으나, GEBR-7B를 처리한 마우스의 경우 대식세포가 감소된 것으로 나타났다(도 3a 참조). As a result, PPD-induced COPD-induced macrophages, which are indicative of inflammatory responses, were increased, but macrophages were decreased in mice treated with GEBR-7B (see FIG. 3A).
또한, 본 발명자들은 면역세포 매개의 염증성 사이토카인인 IL-6 및 TNF-α의 수준을 ELISA 분석을 통해 측정하였는데, 그 결과, 도 3b 및 3c에 나타낸 바와 같이 PPE로 COPD가 유발된 군에서는 이들 염증성 사이토카인의 생성이 증가된 것으로 나타났으나, GEBR-7B의 처리에 의해 증가된 염증성 사이토카인의 생성이 현저하게 감소되는 것으로 나타났다.In addition, the present inventors measured the levels of the immune cell mediated inflammatory cytokines IL-6 and TNF-α through ELISA analysis. As a result, as shown in Figs. The production of inflammatory cytokines has been shown to be increased, but the treatment of GEBR-7B has been shown to significantly reduce the production of increased inflammatory cytokines.
따라서 본 발명자들은 본 발명의 GEBR-7B는 항염증 효과가 있으며, 따라서 만성 염증에 의한 만성폐쇄성 폐질환의 증상을 예방, 개선 및 치료할 수 있음을 알 수 있었다. Accordingly, the present inventors have found that the GEBR-7B of the present invention has an anti-inflammatory effect, and thus can prevent, ameliorate, and treat the symptoms of chronic obstructive pulmonary disease caused by chronic inflammation.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the appended claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.
Claims (7)
상기 화합물은 폐 손상 보호효과 또는 염증성 사이토카인의 생성 억제활성을 갖는 것을 특징으로 하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물.The method of claim 1,
The compound has a protective effect on lung damage or inhibiting the production of inflammatory cytokines, chronic obstructive pulmonary disease (COPD) pharmaceutical composition for the prevention or treatment.
상기 염증성 사이토카인은 IL-6 및 TNF-α인 것을 특징으로 하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물.The method of claim 1,
The inflammatory cytokine is characterized in that IL-6 and TNF-α, a chronic composition for preventing or treating pulmonary obstructive pulmonary disease (COPD).
상기 만성폐쇄성 폐질환(COPD)은 만성폐쇄성기관지염, 만성세기관지염 또는 폐기종(Emphysema)인 것을 특징으로 하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 치료용 약학적 조성물.The method of claim 1,
The chronic obstructive pulmonary disease (COPD) is characterized in that the chronic obstructive bronchitis, chronic bronchiolitis or emphysema (Emphysema), a pharmaceutical composition for the prevention or treatment of chronic obstructive pulmonary disease (COPD).
상기 화합물은 폐 손상 보호효과 또는 염증성 사이토카인의 생성 억제활성을 갖는 것을 특징으로 하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품.The method of claim 5,
The compound has a protective effect on lung damage or inhibiting the production of inflammatory cytokines, health functional foods for the prevention or improvement of chronic obstructive pulmonary disease (COPD).
상기 만성폐쇄성 폐질환(COPD)은 만성폐쇄성기관지염, 만성세기관지염 또는 폐기종(Emphysema)인 것을 특징으로 하는, 만성폐쇄성 폐질환(COPD)의 예방 또는 개선용 건강기능성 식품.The method of claim 5,
The chronic obstructive pulmonary disease (COPD) is characterized in that the chronic obstructive bronchitis, chronic bronchiolitis or emphysema (Emphysema), a functional food for the prevention or improvement of chronic obstructive pulmonary disease (COPD).
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